[go: up one dir, main page]

EP0805157B1 - Derives d'indole et leur utilisation medicinale - Google Patents

Derives d'indole et leur utilisation medicinale Download PDF

Info

Publication number
EP0805157B1
EP0805157B1 EP96932007A EP96932007A EP0805157B1 EP 0805157 B1 EP0805157 B1 EP 0805157B1 EP 96932007 A EP96932007 A EP 96932007A EP 96932007 A EP96932007 A EP 96932007A EP 0805157 B1 EP0805157 B1 EP 0805157B1
Authority
EP
European Patent Office
Prior art keywords
epoxy
indolomorphinan
didehydro
methoxy
hydroxy
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
EP96932007A
Other languages
German (de)
English (en)
Other versions
EP0805157A4 (fr
EP0805157A1 (fr
Inventor
Hiroshi Nagase
Koji Kawai
Takashi Endo
Shinya Ueno
Masayuki Maeda
Satoshi Sakami
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Toray Industries Inc
Original Assignee
Toray Industries Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Toray Industries Inc filed Critical Toray Industries Inc
Publication of EP0805157A1 publication Critical patent/EP0805157A1/fr
Publication of EP0805157A4 publication Critical patent/EP0805157A4/fr
Application granted granted Critical
Publication of EP0805157B1 publication Critical patent/EP0805157B1/fr
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids

Definitions

  • the present invention relates to novel indole derivatives and medical applications thereof.
  • opioid receptors are classified into three types, ⁇ , ⁇ , and ⁇ .
  • ⁇ opioid receptors have been researched only for a short time, and ligands selective to this receptor, especially alkaloid agonists have not yet been found and developed. Accordingly, ⁇ opioid receptors have been lacking in research as compared with the other opioid receptors.
  • antitussive action and analgesic action are attracting attentions.
  • Codeine which is known as a typical antitussive capable of surely stopping coughing, acts on ⁇ opioid receptors while essentially causing severe side effects such as drug dependence, respiratory depression, constipation, and suppression of CNS.
  • codeine acts on ⁇ opioid receptors while essentially causing severe side effects such as drug dependence, respiratory depression, constipation, and suppression of CNS.
  • ⁇ opioid agonists were reported as showing antitussive activity, removal of aversion and psychotomimetic could not be achieved in many cases. Additionally, due to their agonistic properties on the opioid receptors, removal of suppression of CNS is still a problem to be solved. Lately, although some ⁇ opioid antagonists were also reported as showing antitussive activity, they required improvement in antitussive activity for practical use.
  • ⁇ opioid agonists represented by morphine have been used as analgesics.
  • the use of such agonists is, however, allowed only under strict management in view of the above-mentioned side effects.
  • the above-mentioned side effects i.e. aversion and psychotomimetic are also problems to be solved.
  • no alkaloid ⁇ agonist has yet been developed, and its potential as an analgesic has not yet been clarified.
  • the object of the present invention is to provide ⁇ opioid ligands (agonists and antagonists) which have a novel chemical structure, can be used as antitussives and analgesics, and are free from the above-described severe side effects such as drug dependence, respiratory depression, constipation, and suppression of CNS.
  • R 1 examples include hydrogen, an alkyl having 1 to 5 carbon atoms, a cycloalkylmethyl having 4 to 7 carbon atoms, a cycloalkenylmethyl having 5 to 7 carbon atoms, phenyl, naphthyl, a phenylalkyl having 7 to 13 carbon atoms, a phenylalkenyl having 7 to 13 carbon atoms, an alkenyl having 3 to 7 carbon atoms, a furan-2-yl-(C1 to C5)alkyl, and a thiophene-2-yl-(C1 to C5)alkyl.
  • R 2 are hydrogen, hydroxy, acetoxy, propionoxy, methoxy, and ethoxy, while especially preferred are hydrogen, hydroxy, acetoxy, and methoxy.
  • R 3 are hydrogen, hydroxy, acetoxy, propionoxy, methoxy, ethoxy, and benzyloxy, while especially preferred are hydrogen, hydroxy, acetoxy, methoxy, and benzyloxy.
  • an alkylene having 2 to 5 carbon atoms is preferred wherein one carbon atom may be replaced with a nitrogen atom, an oxygen atom, or a sulfur atom.
  • an alkylene having 2 to 5 carbon atoms -(CH 2 ) 2 -O-, and -(CH 2 ) 2 -S-.
  • R 4 and R 5 include fluoro, chloro, bromo, iodo, nitro, an alkyl having 1 to 5 carbon atoms, an alkoxy having 1 to 5 carbon atoms, trifluoromethyl, trifluoromethoxy, cyano, phenyl, a hydroxyalkyl having 1 to 3 carbon atoms, isothiocyanato, SR 6 , SOR 6 , SO 2 R 6 , (CH 2 ) p OR 6 , (CH 2 ) p CO 2 R 6 , SO 2 NR 7 R 8 , CONR 7 R 8 , (CH 2 ) p NR 7 R 8 , and (CH 2 ) p N(R 7 )COR 8 , wherein p is an integer from 0 to 5; R 6 is an alkyl having 1 to 5 carbon atoms; each of R 7 and R 8 is individually hydrogen, an alkyl having 1 to 5 carbon atoms, or a cycloalkylalky
  • both m and n are 0, namely, no substitution is made concerning R 4 and R 5 .
  • at least one pair of adjacent R 4 groups, adjacent R 5 groups, and one R 4 and one R 5 groups may be linked to form a benzene, pyridine, cyclopentane, cyclohexane, or cycloheptane condensed ring, while a benzene condensed ring is especially preferred.
  • preferred examples are hydrogen, an alkyl having 1 to 5 carbon atoms, allyl, and benzyl, while especially preferred are hydrogen and methyl.
  • R 10 and R 11 are linked to form an -O- group, or R 10 is hydrogen while R 11 is hydrogen, hydroxy or methoxy. Especially preferably, these are linked to form an -O- group.
  • examples of pharmacologically acceptable acid addition salts of the above-described indole derivatives include inorganic acid salts such as hydrochloride, sulfate, nitrate, hydrobromide, hydroiodide, and phosphate; carboxylates such as acetate, lactate, citrate, oxalate, glutaric acid salts, malate, tartarate, fumarate, mandelate, maleate, benzoate, and phthalate; and sulfonates such as methanesulfonate, ethanesulfonate, benzenesulfonate, p -toluenesulfonate, and camphorsulfonate.
  • hydrochloride, hydrobromide, phosphate, tartarate, methanesulfonate, and others are preferably used. Also, the present invention is not limited to these examples.
  • specific examples of the compounds employed in the present invention include 17-allyl-6,7-didehydro-4,5 ⁇ -epoxy-3,14 ⁇ -dihydroxy-1',7'-ethylene-6,7,2',3'-indolomorphinan, 17-cyclopropylmethyl-6,7-didehydro-4,5 ⁇ -epoxy-3-hydroxy-14 ⁇ -methoxy-1',7'-ethylene-6,7,2',3'-indolomorphinan, 17-allyl-6,7-didehydro-4,5 ⁇ -epoxy-3-hydroxy-14 ⁇ -methoxy-1',7'-ethylene-6,7,2',3'-indolomorphinan, 17-cyclopropylmethyl-6,7-didehydro-4,5 ⁇ -epoxy-3-methoxy-14 ⁇ -hydroxy-1',7'-ethylene-6,7,2',3'-indolomorphinan, 17-allyl-6,7-didehydro-4,5 ⁇ -epoxy-3
  • indolomorphinan 17-benzyl-6,7-didehydro-4,5 ⁇ -epoxy-3,14 ⁇ -dimethoxy-1',7'-trimethylene-6,7,2',3'-indolomorphinan, 17-butyl-6,7-didehydro-4,5 ⁇ -epoxy-3,14 ⁇ -dimethoxy-1',7'-trimethylene-6,7,2',3'-indolomorphinan, 17-(furan-2-ylmthyl )-6,7-didehydro-4,5 ⁇ -epoxy-3,14 ⁇ -dimethoxy-1',7'-trimethylene-6,7,2',3'-indolomorphinan, 17-cinnamyl-6,7-didehydro-4,5 ⁇ -epoxy-3,14 ⁇ -dimethoxy-1',7'-trimethylene-6,7,2',3'-indolomorphinan, 17-cyclohex
  • the compounds employed in the present invention include 17-allyl-6,7-didehydro-4,5 ⁇ -epoxy-3,14 ⁇ -dihydroxy-1',3"-ethylene-6',7'-benzo-6,7,2',3'-indolomorphinan, 17-cyclopropylmethyl-6,7-didehydro-4,5 ⁇ -epoxy-3-hydroxy-14 ⁇ -methoxy-1',3"-ethylene-6',7'-benzo-6,7,2',3'-indolomorphinan, 17-allyl-6,7-didehydro-4,5 ⁇ -epoxy-3-hydroxy-14 ⁇ -methoxy-1',3"-ethylene-6',7'-benzo-6,7,2',3'-indolomorphinan, 17-cyclopropylmethyl-6,7-didehydro-4,5 ⁇ -epoxy-3-methoxy-14 ⁇ -hydroxy-1',3"-ethylene-6',7'-benzo-6,7,2',3'-
  • the compounds employed in the present invention include 17-allyl-6,7-didehydro-4,5 ⁇ -epoxy-3,14 ⁇ -dihydroxy-1',7'-(2", 3"-benzotrimethylene)-6,7,2',3'-indolomorphinan, 17-cyclopropylmethyl-6,7-didehydro-4,5 ⁇ -epoxy-3-hydroxy-14 ⁇ -methoxy-1',7'-(2", 3"-benzotrimethylene)-6,7,2',3'-indolomorphinan, 17-allyl-6,7-didehydro-4,5 ⁇ -epoxy-3-hydroxy-14 ⁇ -methoxy-1',7'-(2", 3"-benzotrimethylene)-6,7,2',3'-indolomorphinan, 17-cyclopropylmethyl-6,7-didehydro-4,5 ⁇ -epoxy-3-methoxy-14 ⁇ -hydroxy-1',7'-(2",3"-benzotrim
  • a morphinan derivative represented by the above general formula (II) (in the formula, definitions of R 1 , R 2 , R 3 , R 9 , R 10 , and R 11 are the same as the aforementioned definitions) is reacted with a hydrazine derivative represented by the above general formula (III) (in the formula, definitions of-X-, m, n, R 4 , and R 5 are the same as the aforementioned definitions) in a solvent in the presence of an acid catalyst.
  • solvents which can be used herein include alcoholic solvents such as methanol, ethanol,1-propanol, and 2-propanol; aprotic dipolar solvents such as DMF and DMSO; aromatic hydrocarbon solvents such as benzene, toluene, and xylene; ether solvents such as diethyl ether, THF, and DME; halogeno carbon solvents such as dichloroethane, chloroform, carbon tetrachloride, and 1,2-dichloroethane; and organic acids capable of being used as solvents such as acetic acid and propionic acid.
  • alcoholic solvents such as methanol, ethanol,1-propanol, and 2-propanol
  • aprotic dipolar solvents such as DMF and DMSO
  • aromatic hydrocarbon solvents such as benzene, toluene, and xylene
  • ether solvents such as diethyl ether, THF, and DME
  • alcoholic solvents such as methanol, ethanol,1-propanol, and 2-propanol
  • aprotic dipolar solvents such as DMF and DMSO
  • organic acids capable of being used as solvents such as acetic acid and propionic acid.
  • methanol, ethanol, DMF, and acetic acid are especially preferred.
  • Examples of the acid catalyst which can be used in the present invention include inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, and hydroiodic acid; sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p -toluenesulfonic acid, and camphcrsulfonic acid; carboxylic acids such as acetic acid, lactic acid, citric acid, oxalic acid, glutaric acid, malic acid, tartaric acid, fumaric acid, mandelic acid, maleic acid, benzoic acid, and phthalic acid (incidentally, although the reaction may not smoothly progress with calboxylic acid alone, a strong acid may optionally be added as a cocatalyst in such a case); and acidic ion-exchange resin.
  • inorganic acids such as hydrochloric acid, sulfuric acid, nitric
  • hydrochloric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, and acidic ion-exchange resin are preferably used.
  • the amount of the acid catalyst to be added is 1 to 30 equivalent amounts, and preferably,1 to 10 equivalent amounts relative to the total amount of base present in the reaction system.
  • the acid catalyst may be added after converting the base component into salt, or may be added into the reaction mixture in a desired amount.
  • the reaction temperature is 0 to 300°C, preferably 25 to 170°C, and more preferably 60 to 120°C.
  • the compounds of the present invention expressed by the general formula (I) were found to be compounds which act on ⁇ opioid receptors and have a strong antitussive and analgesic activity, as shown with practical examples described below. Accordingly, the compounds of the present invention are expected to serve as effective antitussives and analgesics.
  • the compound may be a free base or a salt thereof, or may be used in combination with suitable excipients such as stabilizers, buffers, diluents, isotonizing agents, and antiseptics.
  • suitable excipients such as stabilizers, buffers, diluents, isotonizing agents, and antiseptics.
  • the antitussive/analgesic agent of the present invention may be orally administered in the form of a tablet, a capsule, a granule, a powder, or a syrup; may be parenterally administered in the form of an injection solution, a suppository, or a liquid; or may be locally administered in the form of an ointment, a cream, or a stupe.
  • the antitussive/analgesic agent of the present invention contains 0.00001 to 90% by weight of the above-described active principle, and more preferably, 0.0001 to 70% by weight.
  • the dosage is optionally determined according to the disease condition, age and body weight of the patient, and the administration method.
  • the dosage for injection is 0.1 ⁇ g to 1 g per day, and the dosage for oral administration is 1 ⁇ g to 10 g. In each case, either single administration or multiple administration can be employed.
  • Naltolexone hydrochloride (383 mg), N-aminoindoline 1a methanesulfonate (375 mg, 1.1 equivalent amounts), and methanesulfonic acid (0.14 ml, 2 equivalent amounts) were mixed in ethanol (8 ml), and refluxed for 8.5 hours. After being allowed to cool, the resultant was poured into a 5% sodium hydroxide solution (20 ml), subjected to extraction with chloroform (20 ml x 3), dried over anhydrous magnesium sulfate, and concentrated.
  • This free base substance was converted into a hydrochloric acid salt in methanol, and the resultant precipitate was collected by filtration to obtain the object product.
  • Example 4 17-Cyclopropylmethyl-6,7-didehydro-4,5 ⁇ -epoxy-3,14 ⁇ -dihydroxy-1',7'-trimethylene-6,7,2',3'-indolomorphinan 4 methanesulfonate (153.9 mg) obtained in Example 4 was dissolved in anhydrous DMF (3 ml). To this solution, anhydrous potassium carbonate (110 mg, 3 equivalent amounts) and methyl iodide (33.3 ⁇ l + 13.3 ⁇ l, total 2.8 equivalent amounts) were added and reacted at-room temperature for 5 hours.
  • anhydrous potassium carbonate 110 mg, 3 equivalent amounts
  • methyl iodide 33.3 ⁇ l + 13.3 ⁇ l, total 2.8 equivalent amounts
  • the resultant was then poured into a mixture of water (10 ml) and ethyl acetate (12 ml) for separation.
  • the aqueous phase was subjected to re-extraction with ethyl acetate (7 ml), and the obtained organic phases were mixed and washed with a saturated sodium chloride solution (10 ml).
  • the resultant was then dried over anhydrous sodium sulfate, and concentrated to obtain a crude product.
  • This crude product was purified by silica gel column chromatography (9385 manufactured by Merck Ltd. 50 g; chloroform) to obtain a free base substance of the object product.
  • Example 11 17-Cyclopropylmethyl-6,7-didehydro-4,5 ⁇ -epoxy-3-methoxy-14 ⁇ -hydroxy-1',7'-trimethylene-6,7,2',3'-indolomorphinan 11 (500 mg) obtained in Example 11 was dissolved in anhydrous THF (20 ml). To this solution, sodium hydride (52 mg,1.1 equivalent amounts) and methyl iodide (500 ⁇ l, 5 equivalent amounts) were added and reacted for 3 hours while refluxing.
  • the resultant was then poured into a mixture of water (50 ml) and chloroform (50 ml) for separation.
  • The-resultant was then dried over anhydrous sodium sulfate, and concentrated to obtain a crude product.
  • This free base substance was dissolved in methanol (5 ml) with the addition of 1 equivalent amount of methanesulfonic acid. Subsequently, the solvent was distilled off, and the resultant was suspended in ether and collected by filtration to obtain the-above-titled compound.
  • Example 29 6,7-Didehydro-4,5 ⁇ -epoxy-3-methoxy-14 ⁇ -hydroxy-1',7'-trimethylene-6,7,2',3'-indolomorphinan 29 (400 mg) obtained in Example 29 was dissolved in anhydrous DMF (5 ml). To this solution, anhydrous potassium carbonate (216 mg,1.5 equivalent amounts) and methyl iodide (65 ⁇ l,1 equivalent amount) were added and reacted at room temperature for 1.5 hours.
  • the resultant was then poured into a mixture of water (50 ml) and ether (50 ml) for separation.
  • the aqueous phase was subjected to re-extraction with ether (20 ml ⁇ 3), and the obtained organic phases were mixed, dried over anhydrous sodium sulfate, and concentrated.
  • This free base substance was dissolved in methanol (5 ml) with the addition of 1 equivalent amount of methanesulfonic acid. Subsequently, the solvent was distilled off, and the resultant was suspended in ether and collected by filtration to obtain the above-titled compound.
  • Example 45 17-Methyl-6,7-didehydro-4,5 ⁇ -epoxy-3-methoxy-14 ⁇ -hydroxy-1',7'-trimethylene-6,7,2',3'-indolomorphinan 45 ( 170 mg) obtained in Example 45 was dissolved in methylene chloride (8 ml). After a methylene chloride solution of boron tribromide (1.0 M,2.60 ml, 6 equivalent amounts) was added at 0°C, the resulting mixture was warmed to room temperature, and stirred at this temperature for 40 min.
  • boron tribromide 1.0 M,2.60 ml, 6 equivalent amounts
  • the reaction mixture was then diluted with methylene chloride (30 ml), a saturated sodium hydrogencarbonate solution (30 ml) was added and stirred, and the mixture was subjected to separation.
  • the aqueous phase was subjected to re-extraction with chloroform, and the obtained organic phases were mixed, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product.
  • This free base substance was dissolved in methanol (3 ml) with the addition of methanesulfonic acid, suspended in ether, and collected by filtration to obtain the object product.
  • VMD mouse vas deferens
  • mice Male ddy strain mice were used in this experiment. Each of the vas deferens isolated from the mice was hung in a Magnus tube which was filled with a Krebes-Henseleit solution (NaCl 118 nM; KCl 4.7 mM; CaCl 2 2.5 mM; KH 2 PO 4 1.1 mM; NaHCO 3 25 mM; glucose 11 mM), and aerated with a gas of 5% carbon dioxide and 95% oxygen and maintained at 37°C. Electric stimulation was applied through upper and lower ring-shaped platinum electrodes at 0.1 Hz and 5.0 mS. Tissue contraction was recorded on a polygraph using an isometric transducer.
  • a Krebes-Henseleit solution NaCl 118 nM; KCl 4.7 mM; CaCl 2 2.5 mM; KH 2 PO 4 1.1 mM; NaHCO 3 25 mM; glucose 11 mM
  • Electric stimulation was applied through upper and lower ring-shaped
  • DPDPE was added in a cumulative manner to determine the IC 50 value (concentration for 50% inhibition of contraction induced by electric stimulation).
  • IC 50 value concentration for 50% inhibition of contraction induced by electric stimulation
  • 100 nM of a sample compound was added to the system beforehand, and 20 minutes later, DPDPE was added in a cumulative manner.
  • the ratio of the IC 50 value of DPDPE in the presence of the sample compound to that in the absence of it was determined, and the pA 2 value was calculated in accordance with the Schild, et al.'s method [Schild, H. O., Br. J. Pharmacol. Chamother . 4, 277 (1949)].
  • Cough was induced by forcing rats to inhale capsaicin (60 ⁇ M) which was nebulized by an ultrasonic nebulizer, and fed to caps over the rats'heads through silicone tubes by a respirator. Capsaicin was fed for inhalation at a rate of 70 times/min. and 10 ml each time.
  • capsaicin was inhaled for 5 minutes, and inducement of coughing was confirmed during this period. Thirty minutes after the drug administration, capsaicin was inhaled for 5 minutes, and the number of induced coughs during capsaicin inhalation was counted. Antitussive effect was evaluated by determining an inhibitory ratio, namely, the ratio of the number of coughs after the drug administration to that before the drug administration. Capsaicin was dissolved in saline. Each drug was dissolved in a 10% DMSO solution and intraperitoneally administered. The effect of the drug is expressed with an ED 50 value which is the dosage for 50% cough inhibition.
  • acetic acid solution was intraperitoneally administered at a volume of 0.1 ml/10 g ⁇ body weight.
  • Analgesic activity was evaluated with an index which was the number of writhing reactions occurring over 10 minutes from 10 minutes after administration.
  • the drug to be evaluated was dorsal-subcutaneously administered 15 minutes before the administration of acetic acid.
  • the compound 28 exhibited a strong analgesic activity with a ED 50 value of 16.7 mg/kg.
  • the compounds of the present invention have been found to act on ⁇ -opioid receptors to exhibit strong antitussive and analgesic actions. Accordingly, the compounds of the present invention have been found to be favorable in the pharmaceutical field as effective antitussives and analgesics.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Pain & Pain Management (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Indole Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Claims (11)

  1. Dérivé d'indole représenté par la formule générale (I) suivante ou un sel d'addition d'acide pharmacologiquement acceptable de celui-ci :
    Figure 01440001
       dans laquelle :
    R1 est hydrogène, un alkyle ayant 1 à 5 atomes de carbone, un cycloalkylalkyle ayant 4 à 7 atomes de carbone, un cycloalcénylalkyle ayant 5 à 7 atomes de carbone, un aryle ayant 6 à 12 atomes de carbone, un aralkyle ayant 7 à 13 atomes de carbone, un alcényle ayant 3 à 7 atomes de carbone, un furann-2-ylalkyle dans lequel l'alkyle a 1 à 5 atomes de carbone, ou un thiophène-2-ylalkyle dans lequel l'alkyle a 1 à 5 atomes de carbone ;
    R2 est hydrogène, hydroxyle, un alkoxy ayant 1 à 5 atomes de carbone, ou un alcanoyloxy ayant 1 à 5 atomes de carbone ;
    R3 est hydrogène, hydroxyle, un alkoxy ayant 1 à 5 atomes de carbone, un alcanoyloxy ayant 1 à 5 atomes de carbone ou un aralkyloxy ayant 7 à 13 atomes de carbone ;
    -X- est un pontage comprenant 2 à 5 atomes de carbone, dans lequel au moins un des atomes de carbone peut être remplacé par un atome d'azote, un atome d'oxygène ou un atome de soufre ;
    m est un entier allant de 0 à 3 ;
    n est un entier allant de 0 à 10 ;
    chacun des m radicaux R4 et des n radicaux R5 est individuellement fluoro, chloro, bromo, iodo, nitro, un alkyle ayant 1 à 5 atomes de carbone, un alkoxy ayant 1 à 5 atomes de carbone, trifluorométhyle, trifluorométhoxy, cyano, phényle, un hydroxyalkyle ayant 1 à 3 atomes de carbone, isothiocyanato, SR6, SOR6, SO2R6, (CH2)pOR6, (CH2)pCO2R6, SO2NR7R8, CONR7R8, (CH2)p NR7R8 ou (CH2)p N(R7)COR8, où p est un entier allant de 0 à 5 ; R6 est un alkyle ayant 1 à 5 atomes de carbone ; chaque R7 et R8 est individuellement hydrogène, un alkyle ayant 1 à 5 atomes de carbone, ou un cycloalkylalkyle ayant 4 à 7 atomes de carbone, et parmi les m radicaux R4 et n radicaux R5, au moins une paire de radicaux R4 adjacents, de radicaux R5 adjacents, et un radical R4 et un radical R5 peut être liée pour former un cycle condensé benzène, pyridine, cyclopentane, cyclohexane ou cycloheptane ;
    R9 est hydrogène, un alkyle ayant 1 à 5 atomes de carbone, un alcényle ayant 1 à 5 atomes de carbone, un aralkyle ayant 7 à 13 atomes de carbone, un hydroxyalkyle ayant 1 à 3 atomes de carbone, (CH2)pOR6 ou (CH2)pCO2R6, où p et R6 sont identiques à ci-dessus ;
    R10 et R11 sont liés pour former un radical -O-, -S- ou -CH2-, ou R10 est hydrogène alors que R11 est indépendamment hydrogène, hydroxyle, un alkoxy ayant 1 à 5 atomes de carbone, ou un alcanoyloxy ayant 1 à 5 atomes de carbone; et
    le composé exprimé par la formule générale (I) peut être une forme (+), une forme (-) ou une forme (±).
  2. Dérivé d'indole ou sel d'addition d'acide pharmacologiquement acceptable de celui-ci selon la revendication 1, dans lequel R10 et R11 sont liés pour former un radical -O-.
  3. Dérivé d'indole ou sel d'addition d'acide pharmacologiquement acceptable de celui-ci selon la revendication 1, dans lequel chacun des radicaux R4 et R5 est individuellement fluoro, chloro, bromo, iodo, nitro, un alkyle ayant 1 à 5 atomes de carbone, un alkoxy ayant 1 à 5 atomes de carbone, trifluorométhyle, trifluorométhoxy, cyano, phényle, un hydroxyalkyle ayant 1 à 3 atomes de carbone, isothiocyanato, SR6, SOR6, SO2R6, (CH2)pCO2R6, SO2NR7R8, CONR7R8, (CH2)pNR7R8, où p est un entier allant de 0 à 5 ; R6 est un alkyle ayant 1 à 5 atomes de carbone ; chaque R7 et R8 est individuellement hydrogène, un alkyle ayant 1 à 5 atomes de carbone, ou un cycloalkylalkyle ayant 4 à 7 atomes de carbone.
  4. Dérivé d'indole ou sel d'addition d'acide pharmacologiquement acceptable de celui-ci selon la revendication 1, dans lequel au moins une paire de radicaux R4 adjacents, de radicaux R5 adjacents, et un radical R4 et un radical R5 peut être liée pour former un cycle condensé benzène, pyridine, cyclopentane, cyclohexane ou cycloheptane.
  5. Dérivé d'indole ou sel d'addition d'acide pharmacologiquement acceptable de celui-ci selon la revendication 4, dans lequel au moins une paire de radicaux R4 adjacents, de radicaux R5 adjacents, et d'un radical R4 et d'un radical R5 peut être liée pour former un cycle condensé benzène, cyclopentane, cyclohexane ou cycloheptane.
  6. Dérivé d'indole ou sel d'addition d'acide pharmacologiquement acceptable de celui-ci selon la revendication 4, dans lequel au moins une paire de radicaux R4 adjacents, de radicaux R5 adjacents, et d'un radical R4 et d'un radical R5 peut être liée pour former un cycle condensé pyridine.
  7. Médicament comprenant le dérivé d'indole ou le sel d'addition d'acide pharmacologiquement acceptable de celui-ci selon la revendication 1.
  8. Composition médicinale comprenant une quantité efficace du dérivé d'indole ou du sel d'addition d'acide pharmacologiquement acceptable de celui-ci selon la revendication 1, présent dans un véhicule pharmacologiquement acceptable.
  9. Antitussif comprenant le dérivé d'indole ou le sel d'addition d'acide pharmacologiquement acceptable de celui-ci selon la revendication 1.
  10. Analgésique comprenant le dérivé indole ou le sel d'addition d'acide pharmacologiquement acceptable de celui-ci selon la revendication 1.
  11. Procédé de préparation d'un dérivé d'indole représenté par la formule générale (I) ou du sel d'addition d'acide pharmacologiquement acceptable de celui-ci, comprenant la réaction d'un dérivé de morphinane représenté par la formule générale (II) suivante :
    Figure 01470001
       avec un dérivé d'hydrazine représenté par la formule (III) suivante :
    Figure 01470002
       dans lesquelles les définitions de R1, R2, R3, R9, R10 et R11 dans la formule générale (II) et les définitions de -X-, m, n, R4 et R5 dans la formule générale (III) sont identiques à celles de la revendication 1.
EP96932007A 1995-09-26 1996-09-26 Derives d'indole et leur utilisation medicinale Expired - Lifetime EP0805157B1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP247472/95 1995-09-26
JP24747295 1995-09-26
JP24747295 1995-09-26
PCT/JP1996/002791 WO1997011948A1 (fr) 1995-09-26 1996-09-26 Derives d'indole et leur utilisation medicinale

Publications (3)

Publication Number Publication Date
EP0805157A1 EP0805157A1 (fr) 1997-11-05
EP0805157A4 EP0805157A4 (fr) 1999-01-07
EP0805157B1 true EP0805157B1 (fr) 2003-06-04

Family

ID=17163970

Family Applications (1)

Application Number Title Priority Date Filing Date
EP96932007A Expired - Lifetime EP0805157B1 (fr) 1995-09-26 1996-09-26 Derives d'indole et leur utilisation medicinale

Country Status (13)

Country Link
US (1) US5849731A (fr)
EP (1) EP0805157B1 (fr)
JP (1) JP3123080B2 (fr)
CN (1) CN1093862C (fr)
AT (1) ATE242247T1 (fr)
AU (1) AU712012B2 (fr)
CA (1) CA2205664C (fr)
DE (1) DE69628543T2 (fr)
ES (1) ES2197953T3 (fr)
NO (1) NO972377L (fr)
PT (1) PT805157E (fr)
TW (1) TW344742B (fr)
WO (1) WO1997011948A1 (fr)

Families Citing this family (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1043766C (zh) * 1992-09-29 1999-06-23 东丽株式会社 吲哚衍生物及其制法和它们在制备药物中的应用
CA2383146C (fr) * 1999-08-24 2010-11-16 Hiroshi Nagase Agent therapeutique contre la douleur neuropathique et modele animal de douleur neuropathique
WO2002042309A1 (fr) * 2000-11-22 2002-05-30 Toray Industries, Inc. Dérivés d'indole et leur utilisation dans des médicaments
JPWO2004078177A1 (ja) * 2003-03-07 2006-06-08 東レ株式会社 薬物・物質依存治療薬
BRPI0506548A (pt) * 2004-01-30 2007-05-02 Euro Celtique Sa métodos para produzir compostos de 4-tetrazolil-4-fenilpiperidina
US20090069363A1 (en) * 2004-12-14 2009-03-12 Shionogi & Co. Ltd. A Legal Entity Of Japan Therapeutic Agent for Constipation
WO2008001859A1 (fr) * 2006-06-30 2008-01-03 School Juridical Person Kitasato Gakuen AGONISTE DES RÉCEPTEURS δ DES OPIOÏDES
JP5213157B2 (ja) * 2007-08-24 2013-06-19 学校法人北里研究所 ６，１４−エポキシモルヒナン誘導体およびその医薬用途
ES2784690T3 (es) 2013-12-05 2020-09-29 Univ Bath Nuevos compuestos opioides y sus usos
PT3761982T (pt) 2018-03-08 2024-12-30 Univ Kansas Utilização da nalfurafina no tratamento de doenças desmielinizantes

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0614898A1 (fr) * 1992-09-29 1994-09-14 Toray Industries, Inc. Derive indole, procede pour sa fabrication, et son usage medicinal

Family Cites Families (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4816586A (en) * 1987-07-29 1989-03-28 Regents Of The University Of Minnesota Delta opioid receptor antagonists
US5223625A (en) * 1988-12-22 1993-06-29 Duphar International Research B.V. Annelated indolo [3,2,-C]lactams
US5225417A (en) * 1992-01-21 1993-07-06 G. D. Searle & Co. Opioid agonist compounds
US5354863A (en) * 1992-01-21 1994-10-11 G. D. Searle & Co. Opioid agonist compounds
ATE166229T1 (de) * 1992-12-22 1998-06-15 Toray Industries Antitussivum
US5457208A (en) * 1993-06-21 1995-10-10 Regents Of The University Of Minnesota Kappa opioid receptor antagonists
US5411965A (en) * 1993-08-23 1995-05-02 Arizona Board Of Regents Use of delta opioid receptor antagonists to treat cocaine abuse
US5464841A (en) * 1993-11-08 1995-11-07 Univ Minnesota Use of delta opioid receptor antagonists to treat immunoregulatory disorders
SE9401728D0 (sv) * 1994-05-18 1994-05-18 Astra Ab New compounds II
SE9401727D0 (sv) * 1994-05-18 1994-05-18 Astra Ab New compounds I

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0614898A1 (fr) * 1992-09-29 1994-09-14 Toray Industries, Inc. Derive indole, procede pour sa fabrication, et son usage medicinal

Also Published As

Publication number Publication date
EP0805157A4 (fr) 1999-01-07
NO972377D0 (no) 1997-05-23
CA2205664C (fr) 2008-05-20
CN1093862C (zh) 2002-11-06
WO1997011948A1 (fr) 1997-04-03
DE69628543T2 (de) 2003-12-11
ATE242247T1 (de) 2003-06-15
AU712012B2 (en) 1999-10-28
US5849731A (en) 1998-12-15
CA2205664A1 (fr) 1997-04-03
CN1165517A (zh) 1997-11-19
JP3123080B2 (ja) 2001-01-09
ES2197953T3 (es) 2004-01-16
PT805157E (pt) 2003-10-31
EP0805157A1 (fr) 1997-11-05
NO972377L (no) 1997-07-23
TW344742B (en) 1998-11-11
DE69628543D1 (de) 2003-07-10
AU7096096A (en) 1997-04-17

Similar Documents

Publication Publication Date Title
EP0657163B1 (fr) Antitussif
US6534514B1 (en) Kappa opioid receptor antagonists
JP2004501860A (ja) ノルエピネフリン、ドーパミンおよびセロトニンの再取り込みを遮断するための、４−フェニル置換テトラヒドロイソキノリン類およびその利用
US7538118B2 (en) 6-aminomorphinane derivatives, method for production and use thereof
EP0915094A1 (fr) Derives de morphinane et usage medical de ces derniers
EP1053238B1 (fr) Composes therapeutiques
JPH0648944A (ja) 経口投与のための鎮痛剤
EP0805157B1 (fr) Derives d'indole et leur utilisation medicinale
EP1736157B1 (fr) Derives de morphinane comme agent anti prurit
US5298622A (en) Spiroindane opiate analogs
JP4292738B2 (ja) インドール誘導体およびその医薬用途
US5714483A (en) Antitussive
US6271239B1 (en) Delta opioid receptor-selective benzylidene-substituted morphinans
US6284769B1 (en) Nonpeptide kappa opioid receptor antagonists
EP1200089B1 (fr) Pyridomorphinanes et utilisation
JP2024539106A (ja) 新規方法
US6337330B1 (en) Antitussives
KR20020012314A (ko) 빈뇨 혹은 요실금의 치료 또는 예방제
WO1993021188A1 (fr) Morphinanes substitues par benzylidene selectifs par rapport aux recepteurs opioides delta pour le traitement de l'alcoolisme
AU757975B2 (en) Therapeutic compounds

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 19970521

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE

A4 Supplementary search report drawn up and despatched

Effective date: 19981119

AK Designated contracting states

Kind code of ref document: A4

Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE

17Q First examination report despatched

Effective date: 20020617

GRAH Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOS IGRA

GRAH Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOS IGRA

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

AK Designated contracting states

Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: FI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20030604

REG Reference to a national code

Ref country code: GB

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: CH

Ref legal event code: NV

Representative=s name: DR. LUSUARDI AG

Ref country code: CH

Ref legal event code: EP

REG Reference to a national code

Ref country code: IE

Ref legal event code: FG4D

REF Corresponds to:

Ref document number: 69628543

Country of ref document: DE

Date of ref document: 20030710

Kind code of ref document: P

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: DK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20030904

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: NL

Payment date: 20030917

Year of fee payment: 8

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: BE

Payment date: 20030922

Year of fee payment: 8

Ref country code: AT

Payment date: 20030922

Year of fee payment: 8

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: SE

Payment date: 20030923

Year of fee payment: 8

Ref country code: CH

Payment date: 20030923

Year of fee payment: 8

REG Reference to a national code

Ref country code: SE

Ref legal event code: TRGR

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20030926

Ref country code: IE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20030926

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MC

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20030930

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: GR

Payment date: 20030930

Year of fee payment: 8

REG Reference to a national code

Ref country code: GR

Ref legal event code: EP

Ref document number: 20030403487

Country of ref document: GR

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: PT

Payment date: 20031029

Year of fee payment: 8

REG Reference to a national code

Ref country code: ES

Ref legal event code: FG2A

Ref document number: 2197953

Country of ref document: ES

Kind code of ref document: T3

ET Fr: translation filed
PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

26N No opposition filed

Effective date: 20040305

REG Reference to a national code

Ref country code: IE

Ref legal event code: MM4A

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: AT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20040926

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20040927

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20040930

Ref country code: CH

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20040930

Ref country code: BE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20040930

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: PT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20050328

BERE Be: lapsed

Owner name: *TORAY INDUSTRIES INC.

Effective date: 20040930

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: NL

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20050401

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: GR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20050405

EUG Se: european patent has lapsed
REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

REG Reference to a national code

Ref country code: PT

Ref legal event code: MM4A

Free format text: LAPSE DUE TO NON-PAYMENT OF FEES

Effective date: 20050328

NLV4 Nl: lapsed or anulled due to non-payment of the annual fee

Effective date: 20050401

BERE Be: lapsed

Owner name: *TORAY INDUSTRIES INC.

Effective date: 20040930

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: ES

Payment date: 20090929

Year of fee payment: 14

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: GB

Payment date: 20090923

Year of fee payment: 14

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: DE

Payment date: 20090923

Year of fee payment: 14

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: IT

Payment date: 20090917

Year of fee payment: 14

Ref country code: FR

Payment date: 20091012

Year of fee payment: 14

GBPC Gb: european patent ceased through non-payment of renewal fee

Effective date: 20100926

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20100926

REG Reference to a national code

Ref country code: FR

Ref legal event code: ST

Effective date: 20110531

REG Reference to a national code

Ref country code: DE

Ref legal event code: R119

Ref document number: 69628543

Country of ref document: DE

Effective date: 20110401

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: DE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20110401

Ref country code: FR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20100930

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: GB

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20100926

REG Reference to a national code

Ref country code: ES

Ref legal event code: FD2A

Effective date: 20111019

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: ES

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20100927